Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof

ABSTRACT

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs/compositions of hydrocodone, including benzoates and heteroaryl carboxylic acids, which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/888,587, filed May 7, 2013, which is a continuation of U.S.application Ser. No. 12/828,381, filed Jul. 1, 2010, now U.S. Pat. No.8,461,137, which claims priority to and benefit of U.S. provisionalpatent application No. 61/222,718, filed Jul. 2, 2009, both of which areherein incorporated by reference in their entireties.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Opioids are highly effective as analgesics and are commonly prescribedfor the treatment of acute and chronic pain. They are also commonly usedas antitussives. The opioids, however, also produce euphoria and arehighly addictive. As a result they are often abused with far reachingsocial and health related consequences.

Because of the inherent potential for abuse, it is desirable that anypharmaceutical composition containing an opioid agonist be made asabuse-resistant or abuse-deterrent as practical. Illicit users oftenwill attempt to circumvent the extended release properties of thesedosage forms by injecting or otherwise misusing the product in order toachieve an immediate release of the opioid agonist.

Despite their addictive properties and the potential for abuse,morphine-like drugs, particularly, codeine, hydrocodone, and oxycodonehave been routinely prescribed as treatment for severe acute and chronicpain in recent decades. This is, in part, because there are noalternatives to relieve severe pain that is resistant to other lesspotent analgesics such as non-steroidal anti-inflammatory drugs(NSAIDS). In this regard, there is a need to decrease the abusepotential. Thus far, approaches taken, unfortunately, have not solvedthe problem.

Hydrocodone is an opioid analgesic and antitussive and occurs as fine,white crystals or as crystalline powder. Hydrocodone is a semisyntheticnarcotic analgesic prepared from codeine with multiple actionsqualitatively similar to those of codeine. It is mainly used for reliefof moderate to moderately severe pain. Additionally, it is used as anantitussive in cough syrups and tablets in sub-analgesic doses (2.5-5mg).

Patients taking opioid analgesics such as hydrocodone for pain reliefcan become unintentionally addicted. As tolerance to the opioidsdevelops more drug is needed to alleviate the pain and generate thesense of well being initially achieved with the prescribed dose. Thisleads to dose escalation, which if left unchecked can lead rapidly toaddiction. In some cases patients have become very addicted in as littleas thirty days.

BRIEF SUMMARY OF THE INVENTION

The present technology utilizes covalent conjugation of the opioidhydrocodone with certain aryl carboxylic acids to decrease its potentialfor causing overdose or abuse by requiring the active hydrocodone to bereleased through enzymatic or metabolic breakdown of the conjugate invivo. The present technology also provides methods of deliveringhydrocodone as conjugates that release the hydrocodone following oraladministration while being resistant to abuse by circuitous routes suchas intravenous (“shooting”) injection and intranasal administration(“snorting”).

The presently described technology in at least one aspect provides aslow/sustained/controlled release composition of conjugated hydrocodonethat allows slow/sustained/controlled delivery of the hydrocodone and/orits active metabolite, hydromorphone, into the blood system of a humanor animal within a safe therapeutic window upon, for example, oraladministration. At least some compositions/formulations of the currenttechnology can lessen addiction/abuse potential and/or other common sideeffects associated with hydrocodone and similar compounds.

In one aspect, the present technology provides a composition comprisingat least one conjugate of hydrocodone and at least one benzoic acid orderivative thereof, a salt thereof, or a combination thereof, thebenzoic acid or derivative thereof having the following formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10. In someaspects, the benzoic acid or derivative thereof is an aminobenzoate, ahydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, orcombination thereof.

In another aspect, the present technology provides a compositioncomprising at least one conjugate of hydrocodone and at least onebenzoic acid, a derivative thereof, or a combination thereof.

In yet another aspect, the present technology provides conjugates ofhydrocodone for use to treat pain, preferably moderate to severe pain,or for use to reduce or prevent oral, intranasal or intravenous drugabuse. In some aspects, the conjugates provide oral, intranasal orparenteral drug abuse resistance.

In another aspect, the present technology provides at least oneconjugate of hydrocodone that exhibits a slower rate of release overtime and a greater or equal AUC when compared to an equivalent molaramount of unconjugated hydrocodone over the same time period. In otheraspects, the conjugate of hydrocodone exhibits less variability in theoral PK profile when compared to unconjugated hydrocodone. In yetanother aspect, at least one conjugate has reduced side effects whencompared with unconjugated hydrocodone or prevents drug tampering byeither physical or chemical manipulation.

In another aspect, at least one conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC when comparedto an equivalent molar amount of unconjugated hydrocodone. In furtheraspects, at least one conjugate is provided in an amount sufficient toprovide a therapeutically bioequivalent AUC when compared to anequivalent molar amount of unconjugated hydrocodone but does not providea C_(max) spike or has a lower C_(max) than a therapeutically equivalentamount of unconjugated hydrocodone. In yet a further aspect, at leastone conjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to an equivalent molaramount of unconjugated hydrocodone, but does not provide an equivalentC_(max) spike. In some aspects, at least one conjugate provides anequivalent C_(max) spike when compared to unconjugated hydrocodone.

In yet another aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition requiring ormediated by binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone benzoic acid or derivative thereof, a salt thereof, or a combinationthereof, the benzoic acid or derivative thereof having formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10.

In another aspect, at least one conjugate binds irreversibly to theopioid receptors of the patient. In yet another aspect, at least oneconjugate binds irreversibly to the opioid receptors of the patientwithout a CNS depressive effect.

In a further aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition requiring ormediated by inhibiting binding of an opioid to the opioid receptors ofthe patient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or derivative thereof, a saltthereof, or a combination thereof, the benzoic acid or derivativethereof having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from thegroup consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo,haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl,cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0or 1; and x is an integer between 1 and 10.

In some aspects, the present technology provides at least one conjugatethat reversibly inhibits binding of an opioid to the opioid receptor ofthe patient. In other aspects, at least one conjugate reversiblyinhibits binding of an opioid to the opioid receptor of the patientwithout a CNS depressive effect.

In a further aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition (such aspain) which can be treated by binding of an opioid to the opioidreceptors of the patient, the method comprising orally administering tothe patient a pharmaceutically effective amount of at least oneconjugate of hydrocodone and at least one benzoic acid, a salt thereof,a derivative thereof or a combination thereof.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition (such as addiction)which can be treated by inhibiting binding of an opioid to the opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.

In yet another aspect, the present technology provides a pharmaceuticalkit including a specified amount of individual doses in a packagecontaining a pharmaceutically effective amount of at least one conjugateof hydrocodone and at least one benzoate, a salt thereof, a derivativethereof or a combination thereof, the benzoate having the formula I:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q can be independentlyselected from 0 or 1; and x is an integer between 1 and 10. In someaspects, the kit further comprises instructions for use of the kit in amethod for treating or preventing drug withdrawal symptoms or pain in ahuman or animal patient.

In another aspect, the present technology provides a pharmaceutical kitincluding a specified amount of individual doses in a package containinga pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof. In some aspects, the kit furtherincludes instructions for use of the kit in a method for treating orpreventing drug withdrawal symptoms or pain in a human or animalpatient.

In yet another aspect, the present technology provides a compositioncomprising at least one conjugate of hydrocodone and at least oneheteroaryl carboxylic acid, a derivative thereof, or a combinationthereof.

In yet another aspect, the present technology provides at least oneconjugate of hydrocodone and at least one heteroaryl carboxylic acid, aderivative thereof, or a combination thereof where at least oneheteroaryl carboxylic acid is selected from formula II, formula III orformula IV, wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10. In some aspects,at least one heteroaryl carboxylic acid is a pyridine derivative.

In some aspects, the present technology provides at least one conjugatethat prevents drug tampering by either physical or chemicalmanipulation.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone heteroaryl carboxylic acid.

In a further aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition requiring ormediated by binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone heteroaryl carboxylic acid, where the heteroaryl carboxylic acid isselected from formula II, formula III or formula IV, wherein formula II,formula III and formula IV are:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone nicotinic acid, a derivative thereof, or a combination thereof.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby inhibiting binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid. In someaspects, the heteroaryl carboxylic acid is selected from formula II,formula III or formula IV, wherein formula II, formula III and formulaIV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby inhibiting binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.

In yet another aspect, the present technology provides a pharmaceuticalkit including a specified number of individual doses in a packagecontaining a pharmaceutically effective amount of at least one conjugateof hydrocodone and at least one heteroaryl carboxylic acid, a derivativethereof, or a combination thereof, wherein the heteroaryl carboxylicacid is selected from formula II, formula III or formula IV, whereinformula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10. In some aspects,the kit further comprises instructions for use of the kit in a methodfor treating or preventing drug withdrawal symptoms or pain in a humanor animal patient.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least onebenzoic acid or benzoic acid derivative, a salt thereof, or acombination thereof, the benzoic acid or benzoic acid derivative havingthe following formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10.

In another aspect, the present technology provides a prodrug comprisingat least one conjugate of hydrocodone and at least one benzoic acid, aderivative thereof, or a combination thereof.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least oneheteroaryl carboxylic acid, a derivative thereof, or a combinationthereof. In some aspects, the prodrug includes at least one heteroarylcarboxylic acid selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least onenicotinic acid, a derivative thereof, or a combination thereof.

In some aspects, the prodrug includes an aminobenzoate, ahydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, orcombination thereof.

In some aspects, at least one conjugate binds reversibly to the opioidreceptors of the patient. In some further aspects, at least oneconjugate binds reversibly to the opioid receptors of the patientwithout a CNS depressive effect. In yet another aspect, at least oneconjugate prevents or reduces at least one constipatory side effect ofunconjugated hydrocodone.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1. Chemical structures of hydroxybenzoic acids and benzoic acidderivatives for use in the making of the conjugates of the presenttechnology.

FIG. 2. Chemical structures of aminobenzoic acids for use in the makingof the conjugates of the present technology.

FIG. 3. Chemical structures of aminohydroxybenzoic acids for use in themaking of conjugates of the present technology.

FIG. 4. FIG. 4A is a Table of common hydrocodone products and dosageranges and FIG. 4B is a Table of common hydrocodone products used incough syrups.

FIG. 5. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC (benzoate-hydrocodone), YYFFI-HC(Tyr-Tyr-Phe-Phe-Ile-Hydrocodone) and Diglycolate-HC over time upon oraladministration in rats.

FIG. 6. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, YYFFI-HC, andDiglycolate-HC in rats.

FIG. 7. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC and Adipate-HC over time upon intranasaladministration in rats.

FIG. 8. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon intranasal administration of Bz-HC andAdipate-HC in rats.

FIG. 9. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC, Nicotinate-HC and Hydrocodone•BT over time uponoral administration in rats.

FIG. 10. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, Nicotinate-HCand Hydrocodone•BT in rats.

FIG. 11. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC, 2-ABz-HC and Hydrocodone•BT over time upon oraladministration in rats.

FIG. 12. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, 2-ABz-HC andHydrocodone•BT in rats.

FIG. 13. Synthesis diagrams of conjugates of hydrocodone. FIG. 13Adepicts the synthesis of benzoate hydrocodone. FIG. 13B depicts thesynthesis of nicotinate hydrocodone (nicotinic acid). FIG. 13C depictsthe synthesis of 2-aminobenzoate hydrocodone. FIG. 13D depicts thesynthesis of salicylate hydrocodone.

FIG. 14. PK profile graph of plasma concentrations of intact Bz-HC,active metabolite hydromorphone and of hydrocodone released from Bz-HCover time upon oral administration in rats.

FIG. 15. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC and hydrocodone•BT over time upon oraladministration in dogs.

FIG. 16. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC andhydrocodone•BT in dogs.

FIG. 17. PK profile graph of plasma concentrations of intact Bz-HC andof hydrocodone released from Bz-HC over time upon oral administration indogs.

FIG. 18. PK profile graph of plasma concentrations of intact Bz-HC,active metabolite hydromorphone and of hydrocodone released from Bz-HCover time upon intravenous administration in rats at 0.30 mg/kg.

FIG. 19. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC over time upon oral administration in rats at sixdifferent dosages.

FIG. 20. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC in rats at sixdifferent dosages.

DETAILED DESCRIPTION OF THE INVENTION

The present technology provides compositions comprising aryl carboxylicacids chemically conjugated to hydrocodone (morphinan-6-one,4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs andcompositions of hydrocodone. In some embodiments, the chemical bondbetween these two moieties can be established by reacting the C-6 enoltautomer of hydrocodone with the activated carboxylic acid function ofan aryl carboxylic acid thereby creating an enol-ester conjugate.

The use of “opioid” is meant to include any drug that activates theopioid receptors found in the brain, spinal cord and gut. There are fourbroad classes of opioids: naturally occurring opium alkaloids, such asmorphine (the prototypical opioid) codeine, and thebaine; endogenousopioid peptides, such as endorphins; semi-synthetics such as heroine,oxycodone and hydrocodone that are produced by modifying natural opiumalkaloids (opiates) and have similar chemical structures; and puresynthetics such as fentanyl and methadone that are not produced fromopium and may have very different chemical structures than the opiumalkaloids. Additional examples of opioids are hydromorphone,oxymorphone, methadone, levorphanol, dihydrocodeine, meperidine,diphenoxylate, sufentanil, alfentanil, propoxyphene, pentazocine,nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, andpharmaceutically acceptable salts thereof.

The use of “hydrocodone” is meant to include a semisynthetic narcoticanalgesic and antitussive prepared from codeine with multiple actionsqualitatively similar to those of codeine. It is commonly used for therelief of moderate to moderately severe pain. Trade names includeAnexsia™, Hycodan™, Hycomine™, Lorcet™, Lortab™, Norco™, Tussionex™,Tylox™, and Vicodin™. Other salt forms of hydrocodone, such ashydrocodone bitartrate and hydrocodone polistirex, are encompassed bythe present technology.

Some embodiments of the present technology provide carboxylic acidsconjugated to hydrocodone, where the carboxylic acid group is directlyattached to the aryl moiety. Carboxylic acids directly attached to thearyl moiety include benzoates and heteroaryl carboxylic acids.

Some embodiments of the present technology provide at least oneconjugate of hydrocodone and at least one benzoic acid or benzoic acidderivative, a salt thereof, or a combination thereof. Benzoates arecommon in nature and include, for example but are not limited to,aminobenzoates (e.g., anthranilic acid analogs such as fenamates),aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acidanalogs).

The general structure of benzoic acid and benzoic acid derivatives ofthe present technology is:

where X, Y and Z can be independently any combination of H, O, S, NH or—(CH₂)—; R¹, R² and R³ can be independently any of the following: H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl, and o, p, q can be independently either 0 or 1.

Suitable hydroxybenzoic acids can be found in FIG. 1 and include, butare not limited to, benzoic acid, salicylic acid, acetylsalicylic acid(aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzoic acids are shown in FIG. 2 and include, but are notlimited to, anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid.

Suitable aminohydroxybenzoic acids include, but are not limited to,4-Aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilicacid.

In some embodiments, the composition includes a benzoate conjugatecomprising at least one hydrocodone conjugated to at least one benzoicacid or benzoic acid derivative, salt thereof or combination thereof.

In some embodiments, the benzoates include numerous benzoic acidanalogs, benzoate derivatives with hydroxyl or amino groups or acombination of both. The hydroxyl and amino functions may be present intheir free form or capped with another chemical moiety, preferably butnot limited to methyl or acetyl groups. The phenyl ring may haveadditional substituents, but the total number of substituents can befour or less, three or less, or two or less.

In another embodiment, the prodrug or conjugate composition of thepresent technology is benzoate-hydrocodone, which has the structure:

In yet another embodiment, the present technology provides a prodrug orcomposition comprising at least one conjugate of hydrocodone and atleast one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof. The heteroaryl carboxylic acid can be selected fromformula II, formula III or formula IV where formula II, formula III andformula IV are:

For these formulas, X, Y and Z are independently selected from the groupconsisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ areindependently selected from the group consisting of H, alkyl, alkoxy,aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl,heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o,p, q are independently selected from 0 or 1; and x is an integer from 1to 10.

In some embodiments, the carboxy group of the aryl carboxylic acids canbe attached directly to the aromatic ring. The present technologyincludes both carbon-only aryl groups and aryl groups with heteroatoms(heteroaryl). The aryl or heteroaryl group which is connected directlyto the carboxyl function can be a 6-membered ring and contains no or oneheteroatom. In some embodiments, the additional substituted orunsubstituted aromatic or aliphatic rings can be fused to this6-membered aryl or heteroaryl moiety. In some embodiments, the arylcarboxylic acids may have only one free carboxylic acid group and thetotal number of phenyl substituents on the 6-membered ring should befour or less, for example, 4, 3, 2 or 1.

In some embodiments of the present technology, depending on theindividual aryl carboxylic acid that is connected to hydrocodone, theconjugate of hydrocodone can have a neutral, free acid, free base, orvarious pharmaceutically acceptable anionic or cationic salt forms orsalt mixtures with any ratio between positive and negative components.These salt forms include, but are not limited to: acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.

For the present technology, a suitable conjugate of hydrocodone includesnicotinate-hydrocodone, which has the following structure:

Some embodiments of the present technology provide a conjugate ofhydrocodone that is broken down in vivo either enzymatically orotherwise, releasing the active hydrocodone and the respective arylcarboxylic acid or metabolites thereof. The aryl carboxylic acids usedin the conjugates of the present technology are non-toxic at the givendosing levels and are preferably known drugs, natural products,metabolites, or GRAS (Generally Regarded As Safe) compounds (e.g.,preservatives, dyes, flavors, etc.) or non-toxic mimetics thereof.

Compounds, compositions and methods of the present technology providereduced potential for overdose, reduced potential for abuse or addictionand/or improve hydrocodone's characteristics with regard to hightoxicities or suboptimal release profiles. Without wishing to be limitedto the below theory, the present inventors believe that overdoseprotection may occur due to the conjugates being exposed to differentenzymes and/or metabolic pathways by oral administration where theconjugate is exposed through the gut and first-pass metabolism asopposed to exposure to enzymes in the circulation or mucosal membraneswhich limits the ability of the hydrocodone from being released from theconjugate. Therefore, abuse resistance is provided by limiting the“rush” or “high” available from the active hydrocodone released by theprodrug and limiting the effectiveness of alternative routes ofadministration.

The compositions of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable. Again, not wanting to be bound by anyparticular theory, the bioavailability can be a result of the hydrolysisof the chemical linkage (i.e., a covalent linkage) following oraladministration. In at least one embodiment, release of hydrocodone isreduced when the composition of the present technology is delivered byparenteral routes.

For example, in one embodiment, the composition of the presenttechnology maintains its effectiveness and abuse resistance followingthe crushing of the tablet, capsule or other oral dosage form. Incontrast, from parental non-conjugated (or “unconjugated”) forms ofhydrocodone, the hydrocodone is released immediately following crushingallowing the content of the crushed tablet to be used by injection orsnorting producing the “rush” effect sought by addicts.

In some embodiments of the present technology, the conjugates ofhydrocodone can be given orally to an animal or human patient, and, uponadministration, release the active hydrocodone by being hydrolyzed inthe body. Not to be bound by any particular theory, it is believed thatsince the aryl carboxylic acids are naturally occurring metabolites ormimetics thereof or pharmaceutically active compounds, these conjugatescan be easily recognized by physiological systems resulting inhydrolysis and release of hydrocodone. The conjugates themselves haveeither no or limited pharmacological activity as a conjugate andconsequently may follow a metabolic pathway that differs from the parentdrug.

In some embodiments of the present technology, the choice of a suitablearyl carboxylic acids (“ligands”) to conjugate to hydrocodone determinesthe release of hydrocodone into the systemic circulation and can becontrolled even when the conjugate is administered via routes other thanoral. In one embodiment, the modified hydrocodone would releasehydrocodone similar to free or unmodified hydrocodone. In anotherembodiment, the conjugated hydrocodone releases hydrocodone in acontrolled or sustained form. In some embodiments, this controlledrelease can alleviate certain side-effects and improve upon the safetyprofile of the parent drug. These side-effects may include, but are notlimited to, anxiety, bruising, constipation, decreased appetite,difficulty breathing, dizziness, drowsiness, dry throat, diarrhea,headache, nausea, stomach cramps, stomach pain, vomiting. In anotherembodiment, the conjugated hydrocodone would selectively allowhydrocodone to be metabolized to hydromorphone. In some embodiments,these conjugates can be used for pain relief, such as moderate to severepain relief.

Hydrocodone and other opioids are also highly addictive and prone tosubstance abuse. Recreational drug abuse of opioids is a common problemand usually begins with oral doses taken with the purpose of achievingeuphoria (“rush”, “high”). Over time the drug abuser often increases theoral dosages to attain more powerful “highs” or to compensate forheightened opioid tolerance. This behavior can escalate and result inexploring of other routes of administration such as intranasal(“snorting”) and intravenous (“shooting”).

In some embodiments of the present technology, the hydrocodone that isconjugated with a suitable aryl carboxylic acid ligand does not resultin rapid spikes in plasma concentrations after oral administration thatis sought by a potential drug abuser. In some embodiments, hydrocodonereleased from these conjugates has a delayed T_(max) and possibly lowerC_(max) than the unconjugated hydrocodone. Not to be bound by anyparticular theory, it is believed that the conjugates of the presenttechnology, when taken orally or by other non-oral routes, do notprovide the feeling of a “rush” even when taken at higher doses butstill maintain pain relief.

Additionally, in some embodiments, hydrocodone conjugated withappropriate ligands of the present technology is not hydrolyzedefficiently when administered via non-oral routes. As a result, theseconjugates do not generate high plasma or blood concentrations ofreleased hydrocodone when injected or snorted compared to freehydrocodone administered through these routes.

In some embodiments, the conjugates of the present technology, sincethey consist of covalently bound hydrocodone, are not able to bephysically manipulated to release the hydrocodone opioid from theconjugated hydrocodone by methods, for example, of grinding up orcrushing of solid forms. Further, the conjugates of the presenttechnology exhibits resistance to chemical hydrolysis under conditions apotential drug abuser may apply to “extract” the active portion of themolecule, for example, by boiling, or acidic or basic solution treatmentof the conjugate.

The compositions and prodrugs of the present technology can be oraldosage forms. These dosage forms include but are not limited to tablet,capsule, caplet, troche, lozenge, powder, suspension, syrup, solution ororal thin film (OTF). Preferred oral administration forms are capsule,tablet, solutions and OTF.

Solid dosage forms can include, but are not limited to, the followingtypes of excipients: antiadherents, binders, coatings, disintegrants,fillers, flavors and colors, glidants, lubricants, preservatives,sorbents and sweeteners.

Oral formulations of the present technology can also be included in asolution or a suspension in an aqueous liquid or a non-aqueous liquid.The formulation can be an emulsion, such as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The oils can be administeredby adding the purified and sterilized liquids to a prepared enteralformula, which is then placed in the feeding tube of a patient who isunable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example bydispersing the formulation in an appropriate vehicle (vegetable oils arecommonly used) to form a high viscosity mixture. This mixture is thenencapsulated with a gelatin based film using technology and machineryknown to those in the soft gel industry. The individual units so formedare then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations with excipients designed to form a relatively soft,flavored, tablet dosage form that is intended to be chewed rather thanswallowed. Conventional tablet machinery and procedures, for example,direct compression and granulation, i.e., or slugging, beforecompression, can be utilized. Those individuals involved inpharmaceutical solid dosage form production are versed in the processesand the machinery used, as the chewable dosage form is a very commondosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing theformulation with excipients intended to add binding qualities todisintegration qualities. The mixture is either directly compressed orgranulated then compressed using methods and machinery known to those inthe industry. The resultant compressed tablet dosage units are thenpackaged according to market need, for example, in unit dose, rolls,bulk bottles, blister packs, etc.

The present technology also contemplates the use ofbiologically-acceptable carriers which may be prepared from a wide rangeof materials. Without being limited to, such materials include diluents,binders and adhesives, lubricants, plasticizers, disintegrants,colorants, bulking substances, flavorings, sweeteners and miscellaneousmaterials such as buffers and adsorbents in order to prepare aparticular medicated composition.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons working in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants. Such antioxidants would be food acceptable and couldinclude vitamin E, carotene, BHT or other antioxidants.

Other compounds which may be included by admixture are, for example,medically inert ingredients, e.g., solid and liquid diluents, such aslactose, dextrose, saccharose, cellulose, starch or calcium phosphatefor tablets or capsules, olive oil or ethyl oleate for soft capsules andwater or vegetable oil for suspensions or emulsions; lubricating agentssuch as silica, talc, stearic acid, magnesium or calcium stearate and/orpolyethylene glycols; gelling agents such as colloidal clays; thickeningagents such as gum tragacanth or sodium alginate, binding agents such asstarches, arabic gums, gelatin, methylcellulose, carboxymethylcelluloseor polyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulfates; and other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable, flavoring,preserving, suspending, thickening or emulsifying agents can beincluded.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolize to glucose orwhich metabolize only a very small amount to glucose. The suspensionsand the emulsions may contain a carrier, for example a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol.

Current approved formulations of hydrocodone are combination therapiesof hydrocodone and one or more other non-narcotic active ingredientdepending on intended indication. Examples of these activepharmaceuticals include, but are not limited to, acetaminophen,phenylpropanolamine, homatropine, ibuprofen, aspirin, pheniramine,chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine andguaifenesin. The conjugated hydrocodone of the present technology can beformulated with one or a combination of these or other active substancesor as standalone active ingredient without any other actives.

The conjugate compositions or prodrugs may be used in methods oftreating a patient having a disease, disorder or condition requiring ormediated by binding or inhibiting binding of an opioid to the opioidreceptors of the patient. Treatment comprises orally administering tothe patient a pharmaceutically effective amount of at least oneconjugate of hydrocodone as described in the present technology. Theconjugate can exhibit a slower rate of release over time and AUC whencompared to an equivalent molar amount of unconjugated hydrocodone. Inother embodiments, at least one conjugate can exhibit less variabilityin the oral PK profile when compared to unconjugated hydrocodone.

In other embodiments, at least one conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC (area underthe curve) when compared to a molar equivalent amount of unconjugatedhydrocodone. In further embodiments, the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent AUC whencompared to unconjugated hydrocodone but has a lower C_(max) (peakconcentration) in plasma or does not provide an equivalent C_(max) inplasma concentrations. In some aspects, the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent C_(max)when compared to unconjugated hydrocodone.

Suitable diseases, disorders or conditions that can be treated by theprodrugs or compositions of the present technology are narcoticaddiction or drug addiction and/or acute or chronic pain.

Dosages for the conjugates of the present technology depend on theirmolecular weight and the respective weight-percentage of hydrocodone aspart of the whole conjugate, and therefore can be higher than thedosages of free hydrocodone. Dosages can be calculated based on thestrengths of dosages of hydrocodone bitartrate which range between 2.5mg and 15 mg per dose. Dose conversion from hydrocodone bitartrate tohydrocodone prodrug can be performed using the following formula:dose(HC prodrug/conjugate)=[dose(HC bitartrate)×(molecular weight(HCprodrug/conjugate)/494.49)]/proportion of hydrocodone released fromprodrug/conjugate

HC: Hydrocodone

Suitable dosages of the conjugated hydrocodone of the present technologyinclude, but are not limited to, formulations including from about 0.5mg or higher, alternatively from about 2.5 mg or higher, alternativelyfrom about 5.0 mg or higher, alternatively from about 7.5 mg or higher,alternatively from about 10 mg or higher, alternatively from about 20 mgor higher, alternatively from about 30 mg or higher, alternatively fromabout 40 mg or higher, alternatively from about 50 mg or higher,alternatively from about 60 mg or higher, alternatively from about 70 mgor higher, alternatively from about 80 mg or higher, alternatively fromabout 90 mg or higher, alternatively from about 100 mg or higher, andinclude any additional increments thereof, for example, 0.1, 0.2, 0.25,0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9 or 1.0 mg and multiplied factorsthereof, (e.g., ×1, ×2, ×2.5, ×5, ×10, ×100, etc). The presenttechnology also includes dosage formulations including currentlyapproved formulations of hydrocodone (See FIG. 4), where the dosage canbe calculated using the above-noted formula determined by the amount ofhydrocodone bitartrate. The present technology provides for dosage formsformulated as a single therapy or as a combination therapy with otherAPI's (FIG. 4).

The conjugates of hydrocodone with derivatives of benzoic acid ornicotinic acid of the present technology have a number of advantagesincluding, but not limited to, a reduced patient variability of plasmaconcentrations of hydrocodone or hydromorphone when compared to freehydrocodone, reduced drug abuse potential, reduced risk of chemical orphysical manipulation resulting in full dosage of hydrocodone released,improved dosage forms through covalent linkage to carboxylic acids orderivatives thereof, increased or decreased metabolism of hydrocodone tohydromorphone and/or decreased side-effects other than drug abuse.

Hydrocodone is a narcotic analgesic, which acts as weak agonist atopioid receptors in the central nervous system (CNS). It primarilyaffects the μ (mu) receptor (OP3), but also exhibits agonist activity atthe δ (delta) receptor (OP1) and κ (kappa) receptor (OP2). Additionally,hydrocodone displays antitussive properties by suppressing the coughreflex in the medullary cough center of the brain.

Side effects of opioid analgesics include gastrointestinal dysfunctioncaused by the opioids binding to the mu (μ) receptors present in thegastrointestinal tract. The side-effects in the stomach include areduction in the secretion of hydrochloric acid, decreased gastricmotility, thus prolonging gastric emptying time, which can result inesophageal reflux. Passage of the gastric contents through the duodenummay be delayed by as much as 12 hours, and the absorption of orallyadministered drugs is retarded. In the small intestines the opioidanalgesics diminish biliary, pancreatic and intestinal secretions anddelay digestion of food in the small intestine. Propulsive peristalticwaves in the colon are diminished or abolished after administration ofopioids, and tone is increased to the point of spasm. The resultingdelay in the passage of bowel contents causes considerable desiccationof the feces, which, in turn retards their advance through the colon.These actions, combined with inattention to the normal sensory stimulifor defecation reflex due to the central actions of the drug, contributeto opioid-induced constipation.

Hydrocodone is used for the treatment of moderate to moderately severepain and for inhibition of cough (especially dry, nonproductive cough).The prodrugs of the present technology may be administered for therelief of pain or cough depression or for the treatment of any conditionthat may require the blocking of opioid receptors.

The conjugates of the present technology can provide a decrease in sideeffects of the opioid analgesic, including reduced or inhibitedconstipatory effects.

The present technology also provides a method of synthesis for thepreparation of the conjugated hydrocodone of the present technology. Inone embodiment, the synthesis of the present technology includes thesteps of:

-   -   1. Protection of the ligand, if necessary;    -   2. Activation of the ligand carboxylic acid group, if not        already in activated form;    -   3. Addition of the activated ligand to hydrocodone or vice versa        in the presence of base; and    -   4. Removal of ligand protecting groups, if applicable.

If the aryl carboxylic acid contains any additional reactive functionalgroups that may interfere with the coupling to hydrocodone, it may benecessary to first attach one or more protecting groups. Any suitableprotecting group may be used depending on the type of functional groupand reaction conditions. Some protecting group examples are: acetyl(Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM),p-methoxybenzyl ether (PMB), trimethylsilyl (TMS),tert.-butyldimethylsilyl (TBDPS), triisopropylsilyl (TIPS),carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz),tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Temporary formation ofacetals or ketals from carbonyl functions may also be appropriate.

The carboxylic acid group of the ligands should be activated in order toreact with hydrocodone and to generate appreciable amounts of conjugate.This activation can be accomplished in numerous ways by a variety ofcoupling agents known to one skilled in the art. Examples of suchcoupling agents are: N,N-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI),N,N′-diisopropylcarbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI) orother carbodiimides;(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) or other phosphonium-based reagents;O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH),N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU)or other aminium-based reagents. The aryl carboxylic acid can also beconverted to a suitable acyl halide, acyl azide or mixed anhydride.

A base may be required at any step in the synthetic scheme of an arylcarboxylic acid conjugate of hydrocodone. Suitable bases include but arenot limited to: 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine(DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide,lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g.,potassium tert.-butoxide), any alkali metal hydride (e.g., sodiumhydride), any alkali metal alkoxide (e.g., sodium methoxide),triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction in the syntheticscheme of an aryl carboxylic acid conjugate of hydrocodone include butare not limited to: acetone, acetonitrile, butanol, chloroform,dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO),dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane,methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropylacetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, the prodrug is hydrophobic and thus poorly watersoluble. This results in a gel-like consistency or clumpy suspensionwhen the compound is mixed with water. Examples of these prodrugsinclude, but are not limited to, Piperonylate-HC, 3-OH-4-MeO-Bz-HC,3-OH-Bz-HC and Gallate-HC. These prodrugs cannot be dosed intranasallyin rats due to their lack of water solubility. Not to be bound by anytheory, it is assumed that these compounds would also congeal or becomeclumpy when a human subject tries to inhale them intranasally(“snorting”). This property would not only make an attempt of intranasalabuse an unpleasant experience but would likely also prevent the prodrugfrom permeating the nose mucosa. As a consequence, these compoundsbecome ineffective for this route of administration.

The present technology provides pharmaceutical kits for the treatment orprevention of drug withdrawal symptoms or pain in a patient. The patientmay be a human or animal patient. Suitable human patients includepediatric patients, geriatric (elderly) patients, and normativepatients. The kit comprises a specific amount of the individual doses ina package containing a pharmaceutically effective amount of at least oneconjugate of hydrocodone of the present technology. The kit can furtherinclude instructions for use of the kit. The specified amount ofindividual doses may contain from about 1 to about 100 individualdosages, alternatively from about 1 to about 60 individual dosages,alternatively from about 10 to about 30 individual dosages, including,about 1, about 2, about 5, about 10, about 15, about 20, about 25, about30, about 35, about 40, about 45, about 50, about 55, about 60, about70, about 80, about 100, and include any additional increments thereof,for example, 1, 2, 5, 10 and multiplied factors thereof, (e.g., ×1, ×2,×2.5, ×5, ×10, ×100, etc).

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, it is not intended limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

EXAMPLES Example 1 Chemical Stability of Benzoate and HeteroarylCarboxylate Conjugates of Hydrocodone

Exemplary conjugates of hydrocodone of the present technology andcontrol test conjugates not of the present technology were tested forchemical stability under conditions similar to what a potential drugabuser may use to “extract” the active portion of the molecule, forexample dissolved in water, hydrochloric acid or sodium bicarbonateeither at ambient temperature or 100° C. The conjugates were placed in asolution of water at either ambient temperature (about 20° C.) or in anoil bath at 100° C. for one hour and the amount of the conjugate thatwas hydrolyzed under these conditions was measured. Table 1 demonstratesthe results, showing that the conjugates did not release hydrocodone atambient temperature or when heated in water to 100° C. for one hour.

TABLE 1 water^(a) Compound ambient 100° C. 4-OH—Bz—HC 0% 0% 2-Abz-HC 0%0% 4-MeO—Bz—HC 0% 0%

Further, samples of conjugates of hydrocodone of the present technologywere tested and compared with samples of other conjugates not of thepresent technology of hydrocodone (Adipate-HC) for their hydrolysis tohydrocodone after dilution in 1 N hydrochloric acid (HCl) for 1 hour atambient temperature (˜20° C.) or in an oil bath at 100° C. Thepercentages indicate how much of the initial amount of conjugate washydrolyzed under these conditions. The results are shown in Table 2.

TABLE 2 %-release in 1N HCl^(a) Compound ambient 100° C. 4-OH—Bz—HC 0%30% 2-Abz-HC 0% 16% 3-OH—4-MeO—Bz—HC 0% 35% 2-OH—Bz—HC 3% 27% Adipate-HC13% 100%

Samples of each conjugate were dissolved in a solution of 5% NaHCO₃ forone hour at either ambient temperature (˜20° C.) or in an oil bath at100° C. The percentages indicate how much of the initial amount ofconjugate was hydrolyzed under these conditions as shown in Table 3 forthe conjugates of the present technology and comparison conjugates notof the present technology (Tyr-Tyr-Phe-Phe-Ile-Hydrocodone (YYFFI-HC) orAdipiate-HC).

TABLE 3 %-release in 5% NaHCO₃ ^(a) Compound ambient 100° C. 4-OH—Bz—HC1% 23% 3-OH—4-MeO—Bz—HC 0% 36% YYFFI-HC 0% 70% Adipate-HC 3% 100%

Example 2 Oral PK Profiles of Conjugated Hydrocodone of the PresentTechnology

Oral PK curves were determined for benzoate-hydrocodone (Bz-HC), aprodrug of the present technology, as compared to two conjugates notwithin the scope of the present technology: YYFFI-HC and Diglycolate-HC.Rats were orally administered an amount of the conjugate equivalent to 2mg/kg of freebase hydrocodone and the plasma concentrations of releasedhydrocodone and of the active metabolite hydromorphone were measuredover time by LC-MS/MS. As shown in FIG. 5, the oral PK curves forreleased hydrocodone were somewhat similar for Bz-HC and YYFFI-HC, buthydrocodone plasma concentrations produced by Bz-HC were mostlysignificantly higher than hydrocodone concentrations generated byDiglycolate-HC (AUC and C_(max) for Bz-HC were approximately 40% and 50%higher, respectively). Additionally, Bz-HC created higher plasmaconcentrations of the more potent active metabolite hydromorphone (FIG.6) than both, YYFFI-HC (AUC and C_(max) for hydromorphone released fromBz-HC were approximately 60% and 80% higher, respectively) andDiglycolate-HC (AUC and C_(max) for hydromorphone released from Bz-HCwere approximately 55% and 180% higher, respectively). This suggeststhat all three compounds undergo a different metabolic pathway and thatBz-HC would have pain relieving effects potentially greater than eitherexample.

Example 3 Intranasal PK Profile of Conjugates of Hydrocodone

Conjugates of hydrocodone of the present technology were tested forabuse resistance capabilities by examining the efficiency of ahydrolysis when administered via routes other than oral. Rats wereintranasally treated with conjugate in an amount equivalent to 2 mg/kgof hydrocodone freebase and the concentration of released hydrocodoneand of the active metabolite hydromorphone in the plasma of the rat weremeasured over time by LC-MS/MS. Hydrocodone plasma concentrations weresignificantly lower for Bz-HC (AUC and C_(max) for hydromorphonereleased from Adipate-HC were approximately 280% and 60% higher,respectively) as shown in FIG. 7. Moreover, Bz-HC produced very lowplasma concentration of hydromorphone when compared to Adipate-HC (AUCand C_(max) for hydromorphone released from Adipate-HC wereapproximately 750% and 660% higher, respectively) as shown in FIG. 8.

Prodrugs of the present technology provide hydrocodone and hydromorphoneplasma concentrations that are significantly lower than respectiveplasma concentration for unbound Hydrocodone-BT or for other prodrugclasses when administered intranasally.

Example 4 Exemplary Intravenous PK Profiles of Conjugates of the PresentTechnology

The conjugates of hydrocodone of the present technology are hydrophobic,for example, Bz-HC, Nicotinate-HC, 4-MeO-Bz-HC, Piperonylate-HC,4-OH-Bz-HC, Salicylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and Gallate-HC.Therefore, these compounds cannot be administered intravenously at oralequivalent doses because they do not dissolve in a practical amount ofwater since injectable compounds must be completely in solution, becauseany solid particle may cause an embolism. The amount of water necessaryto dissolve a desirable amount of conjugate would make an injectionunfeasible and thus the present compositions and prodrugs haveanti-abuse potential as opposed to other hydrocodone conjugates that arewater soluble, such as Adipate-HC and Diglycolate-HC which can beadministered intravenously at oral equivalent doses.

Example 5 Comparison of Oral PK Profiles of Conjugates of Hydrocodone

The plasma concentrations of hydrocodone released from Bz-HC andNicotinate-HC were compared to plasma concentrations of hydrocodonegenerated by unconjugated Hydrocodone•BT after oral administration torats. Rats were treated with conjugate or unconjugated drug in an amountequivalent to 2 mg/kg of hydrocodone freebase and the plasmaconcentration of hydrocodone or hydromorphone was measured by LC-MS/MSas demonstrated in FIGS. 9 and 10 respectively. The oral plasmaconcentration of hydrocodone released from Bz-HC increased similarly tothe hydrocodone plasma concentrations observed with Hydrocodone•BT,until it reached C_(max) (C_(max) was approximately equal for bothcompounds). After T_(max), the hydrocodone plasma concentration forBz-HC decreased in a slower and more controlled fashion than forunconjugated Hydrocodone•BT (FIG. 9 and FIG. 10). Bz-HC had a higher AUC(AUC was approximately 25% higher, FIG. 9) when compared toHydrocodone•BT and similar results were observed for the plasmaconcentrations of the active metabolite hydromorphone (FIG. 10).

Nicotinate-HC, produced hydrocodone and hydromorphone plasmaconcentrations that were below the respective concentrations found forunconjugated Hydrocodone•BT. The corresponding AUC values, however, werewithin the range of bioequivalence for the same dose (based onhydrocodone freebase).

2-ABz-HC demonstrated a different release profile after oraladministration to rats than Bz-HC or the unconjugated drugHydrocodone•BT. Rats were treated with an amount equivalent to 2 mg/kgof hydrocodone freebase and the plasma concentration of hydrocodone orhydromorphone was measured by LC-MS/MS over time as shown in FIG. 11 orFIG. 12 respectively. 2-ABz-HC released hydrocodone very slowlyindicated by a gradual increase of plasma concentration followed by anattenuated decrease (FIG. 11). This resulted in a flattened PK curvewhen compared with Hydrocodone•BT (T_(max) for 2-ABz-HC wasapproximately four times longer, AUC and C_(max) were approximately 35%and 60% lower, respectively). Overall, the PK curve of hydromorphone wasalso flatter for 2-ABz-HC than for Hydrocodone. BT (FIG. 12) but didshow a small initial spike (AUC and C_(max) for 2-ABz-HC wereapproximately 25% and 50% lower, respectively).

Example 6 Determination of Variation in Plasma Concentrations ofBenzoate-Hydrocodone

To determine the variability of the plasma concentration of hydrocodone(HC) and hydromorphone (HM), the coefficient of variation (CV) wascalculated for individual animals that were dosed with an amountequivalent to 2 mg/kg of hydrocodone freebase of benzoate-hydrocodone orthe unconjugated hydrocodone bitartrate (BT) and the plasmaconcentrations of hydrocodone and hydromorphone were measured byLC-MS/MS over time. The CV was calculated by dividing the standarddeviation of plasma concentrations in individual animals by the meanplasma concentrations of all dosed animals for a given time point. The“average CV” is the mean CV for all time points, as shown in Table 4.

TABLE 4 Average CV^(a) Compound HC HM Bz—HC 46 41 Hydrocodone•BT 75 64

The lower average CV for Bz-HC indicates that this prodrug has lowerrelative variability in plasma concentrations of hydrocodone andhydromorphone across all dosed animals and time points than theunconjugated drug, hydrocodone bitartrate.

Example 7 Synthesis of Conjugates of Hydrocodone

Synthesis of Benzoate-Hydrocodone Freebase

To a solution of hydrocodone freebase (0.596 g, 1.99 mmol) intetrahydrofuran (25 mL) was added 1 M LiN(SiMe₃)₂ in tetrahydrofuran(5.98 mL). The resulting orange suspension was stirred at ambienttemperatures for 30 min. after which benzoate-succinic ester (1.25 g,5.98 mmol) was added. The resulting mixture was stirred overnight atambient temperatures and was quenched after 18 h by the addition of 100mL saturated ammonium chloride solution which was allowed to stir foranother 2 h. Ethyl acetate (100 mL) was added to the mixture and washedwith saturated ammonium chloride solution (3×100 mL) and water (1×100mL). Organic extracts were dried over anhydrous MgSO₄, solvent wasremoved and residue was taken up in 2-isopropanol (50 mL). Water wasadded until a solid formed. The resulting mixture was chilled, filteredand dried to obtain benzoate-hydrocodone freebase (0.333 g, 0.826 mmol,42% yield) as a dark brown solid. This synthesis is depicted in FIG.13A.

Synthesis of 2-Boc-Aminobenzoic Succinate:

2-Boc-aminobenzoic acid (2.56 g, 10.8 mmol) and N-hydroxy succinimide(1.37 g, 11.88 mmol) were dissolved in 25 mL of THF. DCC (2.45 g, 11.88mmol) was added in one portion. The reaction was stirred overnight. Thesolid was filtered off and rinsed with acetone (2×10 mL). The filtratewas concentrated to dryness and dissolved in 100 mL of acetone. Theresulting precipitate (DCU) was filtered off and the filtrate wasconcentrated to give a solid, which was collected and rinsed withmethanol (3×4 mL) to yield 3.26 g (90%) of white product.

Synthesis of 2-Boc-Aminobenzoic Acid Ester of Hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL ofanhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5mmol) over 20 min. The mixture was stirred for 30 min. and2-Boc-aminobenzoic succinate (1.50 g, 4.5 mmol) was added in oneportion. The reaction was stirred for 4 hr and subsequently quenchedwith 100 mL of sat. NH₄Cl. The mixture was stirred for 1 hr. andextracted with 200 mL of ethyl acetate. The ethyl acetate layer waswashed with sat. NaHCO₃ (2×80 mL) and 5% brine (80 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (7% MeOH/CH₂Cl₂) to give 449 mg (58%) of anamorphous solid.

Synthesis of 2-Aminobenzoic Acid Ester of Hydrocodone DihydrochlorideSalt:

2-Boc-aminobenzoic acid ester of hydrocodone (259 mg, 0.5 mmol) wasstirred in 4 mL of 4 N HCl/dioxane for 4 hr. The solvent was evaporatedto dryness and to the residue was added 5 mL of ethyl acetate. The solidwas collected and rinsed with ethyl acetate to give 207 mg (84%) ofproduct.

Synthesis of 2-MOM-Salicylic Succinate:

2-MOM-salicylic acid (3.2 g, 17.6 mmol) and N-hydroxysuccinimide (2.23g, 19.36 mmol) were dissolved in 40 mL of THF. DCC (3.99 g, 19.36 mmol)was added in one portion. The reaction was stirred overnight. The solidwas filtered off and rinsed with acetone (2×10 mL). The filtrate wasconcentrated and the residue was recrystallized from 10 mL of methanolto give 2.60 g (53%) of a white solid.

Synthesis of 2-MOM-Salicylic Acid Ester of Hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL ofanhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5mmol) over 20 min. The mixture was stirred for 30 min. and2-MOM-salicylic succinate (1.26 g, 4.5 mmol) was added in one portion.The reaction was stirred for 4 hr. and subsequently quenched with 100 mLof sat. NH₄CI. The mixture was stirred for 1 hr. and extracted with 200mL of ethyl acetate. The ethyl acetate layer was washed with sat. NaHCO₃(2×80 mL) and 5% brine (80 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (8% MeOH/CH₂Cl₂) to give 381 mg (58%) of a syrup.

Synthesis of Salicylic Acid Ester of Hydrocodone Hydrochloride Salt:

To 2-MOM-salicylic acid ester of hydrocodone (380 mg, 0.82 mmol) in 12mL of methanol was added 0.5 mL of conc. HCl (12 N). The reaction wasstirred for 6 hr. The solution was concentrated and residual water wasremoved by coevaporating with methanol (5×5 mL). The resulting residuewas dissolved in 1 mL of methanol followed by 20 mL of ethyl acetate.The cloudy mixture was evaporated to about 4 mL. The resulting solid wascollected and rinsed with ethyl acetate to yield 152 mg (41%) ofproduct.

Example 8 Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, andHydromorphone in Rats

After oral administration of benzoate-hydrocodone (Bz-HC) to rats, PKcurves were determined for intact Bz-HC, hydrocodone, and the activemetabolite hydromorphone. Rats were orally administered an amount of theconjugate equivalent to 2 mg/kg of freebase hydrocodone and the plasmaconcentrations of intact Bz-HC, released hydrocodone, and the activemetabolite, hydromorphone, were measured over time by LC-MS/MS. As shownin FIG. 14, the exposure to intact Bz-HC prodrug was much lower than theexposure to hydrocodone or hydromorphone (the AUC for intact Bz-HC wasapproximately 10% and 3% of the AUC values for hydrocodone andhydromorphone, respectively).

Example 9 Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, andHydromorphone in Dogs

After oral administration of benzoate-hydrocodone (Bz-HC) orHydrocodone•BT to dogs, PK curves were determined for intact Bz-HC(Bz-HC arm only), hydrocodone, and the active metabolite hydromorphone.Dogs were orally administered an amount of Hydrocodone•BT or theconjugate equivalent to 2 mg/kg of freebase hydrocodone. The plasmaconcentrations of intact Bz-HC, released hydrocodone, and the activemetabolite, hydromorphone, were measured over time by LC-MS/MS.

A comparison of plasma concentrations of hydrocodone released from Bz-HCand Hydrocodone•BT is shown in FIG. 15. Overall, the plasmaconcentrations of hydrocodone generated by both compounds were quitesimilar. The systemic exposure to hydrocodone was somewhat reduced forBz-HC when compared to Hydrocodone•BT (the AUC value of hydrocodone forBz-HC was approximately 72% of the AUC value for Hydrocodone•BT). TheC_(max) value of hydrocodone for Bz-HC was approximately 92% of theC_(max) value for Hydrocodone•BT.

A comparison of the plasma concentrations of the active metabolite,hydromorphone, following oral administration of Bz-HC or Hydrocodone•BTis shown in FIG. 16. Systemic exposure and maximum plasma concentrationsof hydromorphone were similar for both compounds. The AUC and C_(max)values of hydromorphone for Bz-HC were approximately 103% and 109% ofthe respective values for Hydrocodone•BT

A comparison the plasma concentrations of intact Bz-HC and hydrocodonereleased from Bz-HC is shown in FIG. 17. Similar to the results seen inrats, the plasma concentrations of intact Bz-HC prodrug in dogs were lowwhen compared to the plasma concentrations of hydrocodone (the AUC valuefor intact Bz-HC was approximately 10% of the AUC value forhydrocodone).

Example 10 Intravenous PK Profiles of Conjugated Hydrocodone,Hydrocodone, and Hydromorphone in Rats

Bz-HC (0.30 mg/kg) was administered intravenously to rats. Due to itspoor water solubility (or solubility in PBS), 0.30 mg/kg was close tothe maximum dose that could be administered intravenously to rats. PKcurves were determined for intact Bz-HC, hydrocodone, and the activemetabolite hydromorphone. The plasma concentrations of intact Bz-HC,released hydrocodone, and the active metabolite, hydromorphone, weremeasured over time by LC-MS/MS. The resulting PK curves are shown inFIG. 18.

Example 11 Oral PK Profiles of Hydrocodone and Hydromorphone FollowingVarious Dosages of Bz-HC in Rats

Bz-HC was orally administered to rats at dosages of 0.25, 0.50, 1.00,2.00, 3.00, or 4.00 mg/kg. The plasma concentrations of hydrocodone orhydromorphone were measured by LC-MS/MS, as demonstrated in FIGS. 19 and20, respectively. The exposures (AUC) to hydrocodone and hydromorphoneat doses of Bz-HC between 0.25 and 4.00 mg/kg were fairly linear. Therespective C_(max) values, however, were more variable, particularly forhydromorphone. The maximum plasma concentrations of hydromorphone didnot significantly change at doses above 2.00 mg/kg of Bz-HC.

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

The compositions, prodrugs, and methods described herein can beillustrated by the following embodiments enumerated in the numberedparagraphs that follow:

1. A composition comprising at least one conjugate of hydrocodone and atleast one benzoic acid or benzoic acid derivative, a salt thereof, or acombination thereof, at least one benzoic acid or benzoic acidderivative having the following formula I:

wherein,

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

2. A composition comprising at least one conjugate of hydrocodone and atleast one benzoic acid, a derivative thereof, or a combination thereof.

3. A composition comprising a benzoate conjugate, wherein the benzoateconjugate comprises at least one hydrocodone conjugated to at least onebenzoic acid or benzoic acid derivative.

4. The composition of paragraph 1, wherein at least one benzoic acid orbenzoic acid derivative is an aminobenzoate, a hydroxybenzoate, anaminohydroxybenzoate, a derivative thereof, or combination thereof.

5. The composition of paragraph 4, wherein the aminobenzoate is selectedfrom the group consisting of: anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid, derivatives thereof and combinationsthereof.6. The composition of paragraph 4, wherein the hydroxybenzoate isselected from the group consisting of salicylic acid, acetylsalicylicacid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid, derivatives thereof and combinationsthereof.7. The composition of paragraph 4, wherein the aminohydroxybenzoate isselected from the group consisting of 4-aminosalicylic acid,3-hydroxyanthranilic acid, 3-methoxyanthranilic acid, derivativesthereof and combinations thereof.8. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is a treatment or preventative composition used to treatnarcotic or opioid abuse or prevent withdrawal.9. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is a pain treatment composition.10. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is moderate to severe pain treatment composition.11. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate reduces or prevents oral, intranasal or intravenous drugabuse.12. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate provides oral, intranasal or parenteral drug abuse resistance.13. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate exhibits an improved rate of release over time and AUC whencompared to unconjugated hydrocodone over the same time period.14. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate exhibits less variability in the oral PK profile when comparedto unconjugated hydrocodone.15. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate has reduced side effects when compared with unconjugatedhydrocodone.16. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate prevents drug tampering by either physical or chemicalmanipulation.17. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is provided in a dosage form selected from the groupconsisting of: a tablet, a capsule, a caplet, a suppository, a troche, alozenge, an oral powder, a solution, an oral film, a thin strip, aslurry, and a suspension.18. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to unconjugatedhydrocodone.19. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and C_(max) compared to an equivalentmolar amount of unconjugated hydrocodone.20. The composition of paragraph 1, 2, 3, or 4, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and a lower C_(max) compared to anequivalent molar amount of unconjugated hydrocodone.21. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 0.5 mg or higher.22. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 2.5 mg or higher.23. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 5 mg or higher.24. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 10 mg or higher.25. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 20 mg or higher.26. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 50 mg or higher.27. The composition of paragraph 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 100 mg or higher.28. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or benzoic acid derivative, asalt thereof, or a combination thereof, the benzoic acid or benzoic acidderivative having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

29. The method of paragraph 28, wherein at least one conjugate exhibitsa slower rate of release over time and greater AUC when compared to anequivalent molar amount of unconjugated hydrocodone over the same timeperiod.

30. The method of paragraph 28, wherein at least one conjugate exhibitsless variability in the oral PK profile when compared to unconjugatedhydrocodone.

31. The method of paragraph 28, wherein at least one conjugate hasreduced side effects when compared with unconjugated hydrocodone.

32. The method of paragraph 28, wherein at least one conjugate isprovided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.33. The method of paragraph 28, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC when compared to a molar equivalent amount ofunconjugated hydrocodone.34. The method of paragraph 28, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC and when compared to a molar equivalent amount ofunconjugated hydrocodone.35. The method of paragraph 28, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC and a lower C_(max) when compared to a molarequivalent amount of unconjugated hydrocodone.36. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 0.5 mg or higher.37. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 2.5 mg or higher.38. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 5 mg or higher.39. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 10 mg or higher.40. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 20 mg or higher.41. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 50 mg or higher.42. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 100 mg or higher.43. The method of paragraph 28, wherein at least one conjugate bindsreversibly to the opioid receptors of the patient.44. The method of paragraph 28, wherein at least one conjugate bindsreversibly to the opioid receptors of the patient without a CNSdepressive effect.45. The method of paragraph 28, wherein at least one conjugate preventsor reduces at least one constipatory side effect of unconjugatedhydrocodone.46. The method of paragraph 28, wherein at least one conjugate exhibitsreduced or prevented constipatory effects when compared withunconjugated hydrocodone.47. The method of paragraph 28, wherein at least one conjugate bindsirreversibly to the opioid receptors of the patient.48. The method of paragraph 28, wherein at least one conjugate bindsirreversibly to the opioid receptors of the patient without a CNSdepressive effect.49. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or benzoic acid derivative, asalt thereof, or a combination thereof, the benzoic acid or benzoic acidderivative having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

50. The method of paragraph 49, wherein at least one conjugatereversibly inhibits binding of an opioid to the opioid receptor of thepatient.

51. The method of paragraph 49, wherein at least one conjugatereversibly inhibits binding of an opioid to the opioid receptor of thepatient without a CNS depressive effect.

52. The method of paragraph 49, wherein at least one conjugate preventsor reduces at least one constipatory side effect of hydrocodone alone.

53. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.54. The method of paragraph 53, wherein at least one conjugate providesa slower rate of release over time and higher AUC when compared to anequivalent molar amount of unconjugated hydrocodone over the same timeperiod.55. The method of paragraph 53, wherein at least one conjugate exhibitsless variability in the oral PK profile when compared to hydrocodonealone.56. The method of paragraph 53, wherein at least one conjugate hasreduced side effects when compared with hydrocodone alone.57. The method of paragraph 53, wherein at least one conjugate isprovided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.58. The method of paragraph 53, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC when compared to hydrocodone alone.59. The method of paragraph 53, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC and C_(max) when compared to hydrocodone alone.60. The method of paragraph 53, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC when compared to hydrocodone alone with a lowerC_(max).61. The method of paragraph 53, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC when compared to hydrocodone alone, but does notprovide an equivalent C_(max).62. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 0.5 mg or higher.63. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 2.5 mg or higher.64. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 5 mg or higher.65. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 10 mg or higher.66. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 20 mg or higher.67. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 50 mg or higher.68. The method of paragraph 53, wherein at least one conjugate ispresent in an amount of from about 100 mg or higher.69. The method of paragraph 53, wherein at least one conjugate bindsreversibly to the opioid receptors of the patient.70. The method of paragraph 53, wherein at least one conjugate bindsreversibly to the opioid receptors of the patient without a CNSdepressive effect.71. The method of paragraph 53, wherein at least one conjugate preventsor reduces at least one constipatory side effect of hydrocodone alone.72. The method of paragraph 53, wherein at least one conjugate exhibitsreduced or prevented constipatory effects.73. The method of paragraph 53, wherein at least one conjugate bindspermanently to the opioid receptors of the patient.74. The method of paragraph 53, wherein at least one conjugate bindspermanently to the opioid receptors of the patient without a CNSdepressive effect.75. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.76. The method of paragraph 75, wherein at least one conjugatereversibly inhibits binding of an opioid to the opioid receptor of thepatient.77. The method of paragraph 75, wherein at least one conjugatereversibly inhibits binding of an opioid to the opioid receptor of thepatient without a CNS depressive effect.78. The method of paragraph 75, wherein at least one conjugate preventsor reduces at least one constipatory side effect of hydrocodone alone.79. A pharmaceutical kit comprising:a specified amount of individual doses in a package containing apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or benzoic acid derivative, asalt thereof, or a combination thereof, the benzoic acid or benzoic acidderivative having the formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q can be independently selected from 0 or 1; and

x is an integer between 1 and 10

80. The kit of paragraph 79, wherein the kit further comprises:

(ii) instructions for use of the kit in a method for treating orpreventing drug withdrawal symptoms or pain in a human or animalpatient.

81. The kit of paragraph 80, wherein the patient is a pediatric patient.

82. The kit of paragraph 80, wherein the patient is an elderly patient.

83. The kit of paragraph 80, wherein the patient is a normative patient.

84. A pharmaceutical kit comprising:

a specified amount of individual doses in a package containing apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.

85. The kit of paragraph 84, wherein the kit further comprises:

(ii) instructions for use of the kit in a method for treating orpreventing drug withdrawal symptoms or pain in a human or animalpatient.

86. The kit of paragraph 85, wherein the patient is a pediatric patient.

87. The kit of paragraph 85, wherein the patient is an elderly patient.

88. The kit of paragraph 85, wherein the patient is a normative patient.

89. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 0.5 mg or higher of at least oneconjugate.

90. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 2.5 mg or higher of at least oneconjugate.

91. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 5.0 mg or higher of at least oneconjugate.

92. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 10 mg or higher of at least oneconjugate.

93. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 20 mg or higher of at least oneconjugate.

94. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 50 mg or higher of at least oneconjugate.

95. The kit of paragraph 79, 80, 84 or 85, wherein the individualdosages comprise at least about 100 mg or higher of at least oneconjugate.

96. The kit of paragraph 79, 80, 84 or 85, wherein the kit comprisesfrom about 1 to about 60 individual doses.

97. The kit of paragraph 79, 80, 84 or 85, wherein the kit comprisesfrom about 10 to about 30 individual doses.

98. A composition comprising at least one conjugate of hydrocodone andat least one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof.

99. The composition of paragraph 98, wherein at least one heteroarylcarboxylic acid is selected from formula II, formula III or formula IV,

wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

100. A composition comprising at least one conjugate of hydrocodone andat least one nicotinic acid, a derivative thereof, or a combinationthereof.

101. The composition of paragraph 98, wherein at least one heteroarylcarboxylic acid is a pyridine derivative.

102 The composition of paragraph 98, wherein the heteroaryl carboxylicacid is selected from the group consisting of, isonicotinic acid,picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid,citrazinic acid, 2,6-dihydroxynicotinic acid, kynurenic acid,xanthurenic acid, 6-hydroxykynurenic acid, 8-methoxykynurenic acid,7,8-dihydroxykynurenic acid, 7,8-dihydro-7,8-dihydroxykynurenic acid,derivatives thereof and combinations thereof.103. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is used to treat drug, narcotic or opioid abuse or preventwithdrawal.104. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is used to treat pain.105. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is used to treat moderate to severe pain.106. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate reduces or prevents oral, intranasal or intravenous drugabuse.107. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate provides oral, intranasal or parenteral drug abuse resistance.108. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate prevents drug tampering by either physical or chemicalmanipulation.109. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate exhibits an improved rate of release over time and AUC whencompared to a molar equivalent of unconjugated hydrocodone alone overthe same time period.110. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate exhibits less variability in the oral PK profile when comparedto a molar equivalent of unconjugated hydrocodone alone.111. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate has reduced side effects when compared with hydrocodone alone.112. The composition of paragraph 98, 99 or 100, wherein the compositionis provided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.113. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to a molar equivalent ofunconjugated hydrocodone alone.114. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and C_(max) when compared tohydrocodone alone.115. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to hydrocodone alone,with a lower C_(max).116. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 0.5 mg or higher.117. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 2.5 mg or higher.118. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 5 mg or higher.119. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 10 mg or higher.120. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 20 mg or higher.121. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 50 mg or higher.122. The composition of paragraph 98, 99 or 100, wherein at least oneconjugate is present in an amount of from about 100 mg or higher.123. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid.124. The method of paragraph 123, wherein at least one heteroarylcarboxylic acid is selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

125. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.126. The method of paragraph 123, 124, or 125, wherein at least oneconjugate exhibits an improved rate of release over time and AUC whencompared to hydrocodone alone over the same time period.127. The method of paragraph 123, 124, or 125, wherein at least oneconjugate exhibits less variability in the oral PK profile when comparedto hydrocodone alone.128. The method of paragraph 123, 124, or 125, wherein at least oneconjugate has reduced side effects when compared to hydrocodone alone.129. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is provided in a dosage from selected from the groupconsisting of: a tablet, a capsule, a caplet, a suppository, a troche, alozenge, an oral powder, a solution, an oral film, a thin strip, aslurry, and a suspension.130. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to an equivalent molaramount of unconjugated hydrocodone.131. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and C_(max) when compared to anequivalent molar amount of unconjugated hydrocodone.132. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and a lower C_(max) compared to thesame molar amount of unconjugated hydrocodone.133. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to hydrocodone alone,but does not provide an equivalent C_(max).134. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 0.5 mg or higher.135. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 2.5 mg or higher.136. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 5 mg or higher.137. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 10 mg or higher.138. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 20 mg or higher.139. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 50 mg or higher.140. The method of paragraph 123, 124, or 125, wherein at least oneconjugate is present in an amount of from about 100 mg or higher.141. The method of paragraph 123, 124, or 125, wherein at least oneconjugate binds reversibly to the opioid receptors of the patient.142. The method of paragraph 123, 124, or 125, wherein at least oneconjugate binds reversibly to the opioid receptors of the patientwithout a CNS depressive effect.143. The method of paragraph 123, 124, or 125, wherein at least oneconjugate prevents or reduces at least one constipatory side effect ofhydrocodone alone.144. The method of paragraph 123, 124, or 125, wherein at least oneconjugate exhibits reduced or prevented constipatory effects.145. The method of paragraph 123, 124, or 125, wherein at least oneconjugate binds permanently to the opioid receptors of the patient.146. The method of paragraph 123, 124, or 125, wherein at least oneconjugate binds permanently to the opioid receptors of the patientwithout a CNS depressive effect.147. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid.148. The method of paragraph 147, wherein at least one heteroarylcarboxylic acid is selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

149. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.150. The method of paragraph 147, 148, or 149, wherein at least oneconjugate reversibly inhibits binding of an opioid to the opioidreceptor of the patient.151. The method of paragraph 147, 148, or 149, wherein at least oneconjugate reversibly inhibits binding of an opioid to the opioidreceptor of the patient without a CNS depressive effect.152. The method of paragraph 147, 148, or 149, wherein at least oneconjugate prevents or reduces at least one constipatory side effect ofhydrocodone alone.153. A pharmaceutical kit comprising:a specified number of individual doses in a package containing apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid, a derivativethereof, or a combination thereof, wherein at least one heteroarylcarboxylic acid is selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

154. The kit of paragraph 153, wherein the kit further comprises:

(ii) instructions for use of the kit in a method for treating orpreventing drug withdrawal symptoms or pain in a human or animalpatient.

155. The kit of paragraph 154, wherein the patient is a pediatricpatient.

156. The kit of paragraph 154, wherein the patient is an elderlypatient.

157. The kit of paragraph 154, wherein the patient is a normativepatient.

158. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 0.5 mg or higher of at least one conjugate.

159. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 2.5 mg or higher of at least one conjugate.

160. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 5.0 mg or higher of at least one conjugate.

161. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 10 mg or higher of at least one conjugate.

162. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 20 mg or higher of at least one conjugate.

163. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 50 mg or higher of at least one conjugate.

164. The kit of paragraph 153 or 154, wherein the individual dosagescomprise at least about 100 mg or higher of at least one conjugate.

165. The kit of paragraph 153 or 154, wherein the kit comprises fromabout 1 to about 60 individual doses.

166. The kit of paragraph 153 or 154, wherein the kit comprises fromabout 10 to about 30 individual doses.

167. A prodrug comprising at least one conjugate of hydrocodone and atleast one benzoic acid or benzoic acid derivative, a salt thereof, a ora combination thereof, the benzoic acid or benzoic acid derivativehaving the following formula I:

wherein,

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

168. A prodrug comprising at least one conjugate of hydrocodone and atleast one benzoic acid, a derivative thereof, or a combination thereof.

169. A prodrug comprising a benzoate conjugate, wherein the benzoateconjugate comprises at least one hydrocodone conjugated to at least onebenzoic acid or benzoic acid derivative.

170. A prodrug comprising at least one conjugate of hydrocodone and atleast one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof.

171. The prodrug of paragraph 170, wherein the heteroaryl carboxylicacid is selected from formula II, formula III or formula IV,

wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

172. A prodrug comprising at least one conjugate of hydrocodone and atleast one nicotinic acid, a derivative thereof, or a combinationthereof.

173. The prodrug of paragraph 167, wherein the benzoic acid derivativeis an aminobenzoate, a hydroxybenzoate, an aminohydroxybenzoate, aderivative thereof, or combination thereof.

174. The composition of paragraph 1 or 2, wherein at least one conjugateexhibits less variability in intranasal PK profiles when compared tounconjugated hydrocodone.

175. The composition of paragraph 1 or 2, wherein at least one conjugateexhibits less variability in the parenteral PK profiles when compared tounconjugated hydrocodone.

176. The composition of paragraph 1 or 2, wherein at least one conjugateexhibits less variability in the intravenous PK profile when compared tounconjugated hydrocodone.

The presently described technology is now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to practice the same. It is to be understood that theforegoing describes preferred embodiments of the technology and thatmodifications may be made therein without departing from the spirit orscope of the invention as set forth in the appended claims.

The invention claimed is:
 1. A composition comprising acetaminophen anda conjugate, wherein the conjugate is benzoate-hydrocodone (Bz-HC)having the following structure:


2. The composition of claim 1, wherein the conjugate is used to treatnarcotic or opioid abuse; to reduce narcotic or opioid withdrawal; totreat moderate to severe pain; to reduce oral, intranasal or intravenousdrug abuse; or to provide oral, intranasal or parenteral drug abuseresistance.
 3. The composition of claim 1, wherein the conjugateexhibits an improved AUC and rate of release over time when compared tounconjugated hydrocodone over the same time period; exhibits lessvariability in the oral PK profile when compared to unconjugatedhydrocodone; or has reduced side effects when compared with unconjugatedhydrocodone.
 4. The composition of claim 1, wherein the conjugate isprovided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.
 5. The composition of claim 1, wherein the conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC when compared to unconjugated hydrocodone.
 6. Thecomposition of claim 1, wherein the conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC and C_(max)when compared to an equivalent molar amount of unconjugated hydrocodone.7. The composition of claim 1, wherein the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent AUC and alower C_(max) when compared to an equivalent molar amount ofunconjugated hydrocodone.
 8. The composition of claim 1, wherein theconjugate is a salt.
 9. The composition of claim 8, wherein the salt isa hydrochloride/chloride.
 10. The composition of claim 1, furthercomprising a biologically acceptable carrier.
 11. The composition ofclaim 1, wherein upon administration, active hydrocodone is releasedfrom the conjugate through first-pass metabolism.
 12. A method fortreating pain in an individual in need thereof comprising the step oforally administering a pharmaceutically effective amount of acomposition comprising acetaminophen and a conjugate, wherein theconjugate is benzoate-hydrocodone (Bz-HC) having the followingstructure:


13. The method of claim 12, wherein the conjugate exhibits an improvedAUC and rate of release over time when compared to unconjugatedhydrocodone over the same time period; exhibits less variability in theoral PK profile when compared to unconjugated hydrocodone; or hasreduced side effects when compared with unconjugated hydrocodone. 14.The method of claim 12, wherein the composition is provided in a dosageform selected from the group consisting of: a tablet, a capsule, acaplet, a suppository, a troche, a lozenge, an oral powder, a solution,an oral film, a strip, a slurry, and a suspension.
 15. The method ofclaim 12, wherein the conjugate is provided in an amount sufficient toprovide a therapeutically bioequivalent AUC when compared tounconjugated hydrocodone.
 16. The method of claim 12, wherein theconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and C_(max) when compared to anequivalent molar amount of unconjugated hydrocodone.
 17. The method ofclaim 12, wherein the conjugate is provided in an amount sufficient toprovide a therapeutically bioequivalent AUC and a lower C_(max) whencompared to an equivalent molar amount of unconjugated hydrocodone. 18.The method of claim 12, wherein the composition is used for treatingpain mediated by binding of an opioid primarily to μ opioid receptors ofthe patient.
 19. The method of claim 18, wherein the conjugate bindsreversibly to the μ opioid receptors of the patient.
 20. The method ofclaim 18, wherein the conjugate binds reversibly to the μ opioidreceptors of the patient without a CNS depressive effect.
 21. The methodof claim 12, wherein the composition also reduces narcotic or opioidabuse.
 22. The method of claim 12, wherein the composition also reducesnarcotic or opioid withdrawal.
 23. The method of claim 12, wherein thecomposition also reduces oral, intranasal or intravenous narcotic oropioid abuse.
 24. The method of claim 12, wherein the composition alsoprovides oral, intranasal or parenteral non corticoid opioid abuseresistance.
 25. A pharmaceutical kit comprising a specified amount ofindividual doses in a package containing a pharmaceutically effectiveamount of acetaminophen and a conjugate, wherein the conjugate isbenzoate-hydrocodone (Bz-HC) having the following structure:


26. The pharmaceutical kit of claim 25, wherein the kit furthercomprises instructions for use of the kit in a method for treating pain.27. The pharmaceutical kit of claim 25, wherein the kit furthercomprises instructions for use of the kit in a method for treatingnarcotic or opioid withdrawal symptoms.
 28. The pharmaceutical kit ofclaim 25, wherein the kit further comprises instructions for use of thekit in a method for reducing narcotic or opioid abuse.
 29. Thepharmaceutical kit of claim 25, wherein the specified amount ofindividual doses comprise from about 1 to about 100 individual dosages.30. The pharmaceutical kit of claim 25, wherein the individual dosescomprise at least about 0.5 mg of the conjugate.